This invention relates to novel pyridine-based compounds which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor xcex2. Further, the present invention relates to methods for using such compounds and to pharmaceutical compositions containing such compounds.
While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, metabolic rate, body temperature and mood, and influence blood levels of serum low density lipoprotein (LDL). Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2,5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, replacement therapy, particularly in older individuals, may be restricted by certain detrimental effects from thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor ligands, particularly agonists of the thyroid hormone receptor could lead to specific therapies for these common disorders, while avoiding the cardiovascular and other toxicity of native thyroid hormones. Tissue-selective thyroid hormone agonists may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the xcex2-form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes xcex1 and xcex2. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TRxcex11, TRxcex21 and TRxcex22 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TRxcex21 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TRxcex12 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TRxcex11 isoform is also widely distributed, although its levels are generally lower than those of the TRxcex21 isoform. Whereas many mutations in the TRxcex2 gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TRxcex1 function have not been found.
A growing body of data suggests that many or most effects of thyroid hormones on the heart, and in particular, on the heart rate and rhythm, are mediated through the xcex1-form of the TRxcex11 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues, are mediated more through the xcex2-forms of the receptor. Thus, a TRxcex2-selective agonist might not elicit the cardiac rhythm and rate influences of the hormones, but would elicit many other actions of the hormones. Applicants believe that the xcex1-form of the receptor is primarily associated with heart rate function for the following reasons:
1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TRxcex2-forms, and high circulating levels of T4 and T3;
2) there was a tachycardia in the only described patient with a double deletion of the TRxcex2 gene (Takeda et al, J. Clin. Endrocrinol. and Metab. 1992, Vol. 74, p. 49);
3) a double knockout TRxcex1 gene (but not xcex2-gene) in mice resulted in a slower mouse heart rate, as compared to control mice; and
4) western blot analysis of human myocardial TRs show presence of the TRxcex11, TRxcex12 and TRxcex22 proteins, but not TRxcex21.
If these indications are correct, then it may be possible that a TRxcex2-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and (6) osteoporosis in combination with a bone resorption inhibitor.
In accordance with the illustrative embodiments and demonstrating features of the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I 
wherein
X is oxygen (xe2x80x94Oxe2x80x94), sulfur (xe2x80x94Sxe2x80x94), sulfoxide (xe2x80x94S(O)xe2x80x94), sulfonyl (xe2x80x94SO2xe2x80x94), CR8R8xe2x80x2 or NR8;
Y is oxygen (xe2x80x94Oxe2x80x94), xe2x80x94NR8, xe2x80x94CH2xe2x80x94 or sulfur (xe2x80x94Sxe2x80x94);
Z is a bond or substituted or unsubstituted C1-4 alkyl;
R1 is halogen, trifluoromethyl, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted amide, sulfone, sulfonamide, aryloxy or C3-7 cycloalkyl, wherein said aryl, heteroaryl or cycloalkyl ring(s) are attached or fused to the aromatic ring;
R1a is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R2 and R3 are each independently hydrogen, halogen, substituted or unsubstituted C1-4 alkyl or substituted or unsubstituted C3-5 cycloalkyl, wherein at least one of R2 and R3 being other than hydrogen;
R4 is hydrogen, halogen, amino, Oxe2x80x94R7, Sxe2x80x94R7 or C1-4 alkyl;
R5 is hydroxyl (xe2x80x94OH), carboxylic acid (xe2x80x94COOH), sulfonic acid (xe2x80x94SO2OH) or phosphonic acid (xe2x80x94PO3H2);
R6 is hydrogen, alkyl, alkanoyl or aroyl (such as acetyl or benzoyl);
R7 is hydrogen or C1-4 alkyl;
R8 for each occurrence is independently hydrogen, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, aryl or substituted aryl, arylalkyl or substituted arylalkyl, alkoxy or hydroxyl; and
R8xe2x80x2 is hydrogen, a bond, alkyl or substituted alkyl, alkenyl or substituted alkenyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo or substituted heterocyclo, aryl or substituted aryl, arylalkyl or substituted arylalkyl, alkoxy or hydroxyl, or R8 and R8xe2x80x2 together form a carbonyl (xe2x80x94COxe2x80x94).
The definition of formula I above includes all prodrug-esters, stereoisomers and pharmaceutically acceptable salts of formula I.
The compounds of formula I are thyroid hormone receptor ligands and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably, the compounds of formula I possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, the compounds of formula I may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene, such as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, skin disorders or diseases and congestive heart failure.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. In particular, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combination with a pharmaceutically acceptable carrier.
Further, in accordance with the present invention, a method is provided for preventing, inhibiting or treating the progression or onset of diseases or disorders associated with the thyroid receptor, particularly, the thyroid receptor-beta, such as the diseases or disorders defined above and hereinafter, wherein a therapeutically effective amount of a compound of formula I is administered to a mammalian, i.e., human patient in need of treatment.
The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s) active in the therapeutic areas described herein.
In addition, a method is provided for preventing, inhibiting or treating the diseases as defined above and hereinafter, wherein a therapeutically effective amount of a combination of a compound of formula I and another compound of the invention and/or another type of therapeutic agent, is administered to a mammalian patient in need of treatment.
Preferably, compounds of this invention include embodiments of formula I wherein
X is oxygen, sulfur, sulfoxide, sulfonyl, xe2x80x94CH2xe2x80x94 or xe2x80x94NHxe2x80x94;
Y is oxygen or xe2x80x94NHxe2x80x94;
R1 is halogen, substituted or unsubstituted C1-6 alkyl, C3-7 cycloalkyl, substituted aryl, aryloxy, substituted amide, sulfone or sulfonamide, wherein R1 is attached ortho to the R6Oxe2x80x94 group;
R2 and R3 are each independently iodo, bromo, chloro or fluoro;
R4 is hydrogen, fluoro, chloro, amino, xe2x80x94OCH3, hydroxyl (xe2x80x94OH) or methyl;
R5 is carboxylic acid; and
R6 is hydrogen.
Other preferred embodiments of the invention include compounds of formula I wherein
X is carbonyl, CHR8 or NR8;
Y is oxygen or xe2x80x94NHxe2x80x94;
R1 is halogen, substituted or unsubstituted C1-6 alkyl, substituted aryl, substituted amide, sulfone, sulfonamide or C3-7 cycloalkyl;
R2 and R3 are independently bromo, chloro or methyl;
R4 is hydrogen, fluoro, chloro, hydroxyl, amino, methoxy or methyl;
R5 is a carboxylic acid; and
R6 is hydrogen.
Further preferred embodiments of the invention include compounds of formula I having the structure: 
wherein
Y is oxygen or xe2x80x94NHxe2x80x94.
R1a is hydrogen, methyl or ethyl;
R2 and R3 are halogen;
R4 is hydrogen, halogen, amino, xe2x80x94OCH3 or hydroxyl; and
R10 is hydrogen, halogen or substituted or unsubstituted C1-4 alkyl.
The following abbreviations have the indicated meanings:
Ar=aryl
Bn=benzyl
DMF=N,N-dimethylformamide
DMSO=dimethyl sulfoxide
Et=ethyl
EtOAc=ethyl acetate
g=gram(s)
h or hr=hour(s)
Me=methyl
M+H=parent plus a proton
min=minute(s)
mL=milliliter
mg=milligram(s)
mol=moles
mmol=millimole(s)
M=molar
Ph=phenyl
RT=room temperature
HPLC=high performance liquid chromatography
NMR=nuclear magnetic resonance
THF=tetrahydrofuran
TFA=trifluoroacetic acid
xcexcL=microliter
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term xe2x80x9cthyroid receptor ligandxe2x80x9d as used herein is intended to cover any moiety which binds to a thyroid receptor. The ligand may act as an agonist, an antagonist, a partial agonist or a partial antagonist. Another term for xe2x80x9cthyroid receptor ligandxe2x80x9d is xe2x80x9cthyromimeticxe2x80x9d.
Unless otherwise indicated, the term xe2x80x9calkyldxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 12 carbons in the normal chain, preferably 1 to 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, or isobutyl, pentyl, hexyl, isohexyl, heptyl; 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl. xe2x80x9cSubstituted alkylxe2x80x9d includes an alkyl group optionally substituted with one or more functional groups which are commonly attached to such chains, such as, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, hydroxy, cyano, nitro, amino, halo, carboxyl or alkyl ester thereof and/or carboxamide, substituted or unsubstituted.
Unless otherwise indicated, the term xe2x80x9calkoxyxe2x80x9d refers to alkyl-Oxe2x80x94. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
The term xe2x80x9carylxe2x80x9d or xe2x80x9cArxe2x80x9d as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including l-naphthyl and 2-naphthyl). xe2x80x9cSubstituted arylxe2x80x9d includes an aryl group optionally substituted through available carbon atoms with one or more groups selected from hydrogen, halo, substituted or unsubstituted alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, hydroxy, amino, nitro, cyano and/or any of the alkyl substituents set out herein.
The term xe2x80x9calkanoylxe2x80x9d refers to alkyl-C(O)xe2x80x94.
The term xe2x80x9caroylxe2x80x9d refers to aryl-C(O)xe2x80x94.
Unless otherwise indicated, the term xe2x80x9caryloxyxe2x80x9d as employed herein, alone or as part of another group, denotes xe2x80x94ORxe2x80x94 wherein R is aryl as defined herein.
The term xe2x80x9cheteroarylxe2x80x9d means a 5- or 6-membered aromatic heterocyclic ring which contains one or more heteroatoms selected from nitrogen, sulfur, oxygen and/or a SO or SO2 group. Such rings may be fused to another aryl or heteroaryl ring and include possible N-oxides. xe2x80x9cSubstituted heteroarylxe2x80x9d includes a heteroaryl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9caminoxe2x80x9d as used herein refers to xe2x80x94NRARB where RA and RB are independently hydrogen, or RA and/or RB may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, carboxyl, halo, alkylthio, heteroaryl, heterocycle, heterocycle(aryl) carboalkyl and the like.
The term xe2x80x9csubstituted amidexe2x80x9d as used herein refers to an amide linkage: xe2x80x94C(O)NR where R is hydrogen or may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, amino, carboxyl, halo, alkylthio, heteroaryl, heterocycle carboalkyl and the like.
The term xe2x80x9csulfonamidexe2x80x9d as used herein refers to a sulfonamide linkage: xe2x80x94SO2NRRxe2x80x2 where R and Rxe2x80x2 are independently hydrogen, or one or both of R and Rxe2x80x2 may optionally be substituents, such as any of the substituents described in the definition of substituted alkyl or substituted amino.
The term xe2x80x9csulfonexe2x80x9d as used herein refers to a sulfone linkage: xe2x80x94SO2R where R is hydrogen or may optionally be a substituent, such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, cyano, nitro, amino, carboxyl, halo, alkylthio, heteroaryl, heterocycle carboalkyl and the like.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloxe2x80x9d as used herein, represents a 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from N, O or S. Exemplary monocyclic heterocyclo groups include 2- and 3-thienyl, 2- and 3-furyl, 2-, 3-, and 4-pyridyl and imidazolyl. The term heterocycle or heterocyclic ring also includes bicyclic rings wherein the five- or six-membered ring containing oxygen and/or sulfur and/or nitrogen atoms as defined above is fused to a benzene ring and the bicyclic ring is attached by way of an available atom. Exemplary bicyclic heterocycle groups include 4-, 5-, 6- or 7-indolyl, 4-, 5-, 6-, or 7-isoindolyl, 5-, 6-, 7- or 8-quinolinyl, 5-, 6-, 7- or 8-isoquinolinyl and 4-, 5-, 6- or 7-benzothiazoyl. xe2x80x9cSubstituted heterocycloxe2x80x9d includes a heterocyclo group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
Unless otherwise indicated, the term xe2x80x9calkenylxe2x80x9d as used herein refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons, and more preferably 2 to 8 carbons in the normal chain, which include one or more double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like. xe2x80x9cSubstituted alkenylxe2x80x9d includes an alkenyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9carylalkylxe2x80x9d refers to alkyl groups as described above having an aryl substituent. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl and the like. xe2x80x9cSubstituted arylalkylxe2x80x9d includes an arylalkyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkenylxe2x80x9d as used herein includes saturated or partially saturated (containing one or more double bonds) cyclic hydrocarbon groups containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. xe2x80x9cSubstituted cycloalkylxe2x80x9d or xe2x80x9csubstituted cycloalkenylxe2x80x9d include a cycloalkyl or cycloalkenyl group optionally substituted with one or more substituents, such as those described for substituted alkyl and/or substituted aryl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group-refers to chlorine, bromine, fluorine and iodine, with chlorine or bromine being preferred.
The (CH2)n group is an alkyl group that includes 0 to 4 carbons in the normal chain which may include 1, 2, or 3 alkyl substituents.
The term xe2x80x9ccarbonylxe2x80x9d, as used herein, refers to a xe2x80x94C(O)xe2x80x94 group.
The compounds of formula I can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methyl- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolainine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
Preferred salts of the compounds of formula I which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
The compounds of formula I may also have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., the compound of formula I) is a prodrug within the scope and spirit of the invention.
Various forms of prodrugs are well known in the art. A comprehensive description of prodrugs and prodrug derivatives may be found in:
a.) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996);
b.) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); and
c.) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers, 1991).
Said references are incorporated herein by reference.
Embodiments of prodrugs suitable for use in the present invention include lower alkyl esters, such as ethyl ester, or acyloxyalkyl esters such as pivaloyloxymethyl (POM).
An administration of a therapeutic agent of the invention includes administration of a therapeutically effective amount of the agent of the invention. The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein refers to an amount of a therapeutic agent to treat or prevent a condition treatable by administration of a composition of the invention. That amount is the amount sufficient to exhibit a detectable therapeutic or preventative or ameliorative effect. The effect may include, for example, treatment or prevention of the conditions listed herein. The precise effective amount for a subject will depend upon the subject""s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, it is not useful to specify an exact effective amount in advance.
The compounds of formula I of the invention can be prepared as shown in the following reaction schemes and description thereof, as well as by relevant published literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples. Protection and deprotection in the Schemes below may be carried out by procedures generally known in the art. For example, see T. W. Greene and P. G. M. Wuts, xe2x80x9cProtecting Groups in Organic Synthesisxe2x80x9d, 3rd Edition, (Wiley, 1999), incorporated herein by reference. 
Scheme 1 depicts a general synthetic approach to compounds of formula I wherein X=O, S or NR8, which utilizes the displacement reaction of an appropriately substituted phenol, thiophenol or aniline 1 such as 3-isopropyl-4-methoxyphenol or 4-methoxynaphthol with a pentasubstituted pyridine 2 such as 3,5-dichloro-2,4,6-trifluoropyridine or pentafluoro pyridine to provide intermediate 3. In structure 1 and all other applicable structures contained in further schemes described below, the term xe2x80x9cPGxe2x80x9d refers to a protecting group appropriate for the functional group indicated (in this instance, for a phenolic oxygen). Subsequent displacement of the 2-fluoro and 6-fluoro substituents on the pyridine 3 with nucleophiles 4 and reactant HR4 sequentially provide intermediates 5 and 6 respectively. Examples of suitable nucleophiles 4 include, but are not limited to, glycine methyl ester and methyl glycolate. Examples of reactant HR4 include, but are not limited to, alkylthiol, sodium alkoxide, alkylamine, or benzylamine. Compounds of formula I wherein X is sulfoxide or sulfonyl can be derived from intermediates 5 or 6 when X is S, via oxidation with an oxidating agent, for example mCPBA. Further protecting group and functional group manipulation of intermediates 5 or 6 will provide the compounds of formula I where X is O, S, NR8, sulfoxide and sulfonyl.
For example, where intermediate 1 is 3-isopropyl-4-methoxy phenol (X is oxygen) and intermediate 2 is 3, 5-dichloro-2,4,6-trifluoro pyridine (R2 and R3 are chlorine), the resulting intermediate 3 would be the corresponding diaryl ether where X=O and R2=R3=Cl. The 2-fluoro substituent of this intermediate can be readily displaced with nucleophile 4 where Y is O, NR8, CH2 or sulfur, such as an amine or alkoxide, to form intermediate 5. The 6-fluoro substituent of the resulting amino or alkoxypyridine 5 can then be further displaced with a third nucleophile, such as ethylthiol in presence of potassium carbonate to provide the intermediate 6. Deprotection or Raney-Nickel desulfurization of 5 and/or 6 would provide the desired compounds of formula I wherein R4=F or H.
Poly-substituted prime rings may be prepared by using commerically available polysubstituted phenols as illustrated below in Scheme 1 b where X represents a halogen. 
Alternatively, poly-substitutions can be achieved by halogenation of intermediate Ia or its acyl derivative, intermediate Iia, followed by hydrolysis. Conversion of the halogens (X) to an alkyl, aryl or heteroaryl may be achieved by subsequent Steele or Suzuki coupling reactions with tetraalkyltin or aryl boronic acid reagents. 
Scheme 2 depicts another general synthetic approach to produce the compounds of formula I wherein X=O in which the position adjacent (ortho) to Oxe2x80x94PG (R1=H) can be functionalized via sulfonation/sulfonylation, brominalion or formylation to provide intermediate 7, 8 and 9. Conversion of CHO to COOH and to N-substituted amide may be carried out by methods well known in the art, such as oxidation of the formyl group of intermediate 9 to form intermediate 10. Carbodiimide promoted coupling of an amine with the resulting carboxylic acid of intermediate 10 provides intermediate 11 wherein R1=an amide. Subsequent displacement of the 2-fluoro substituent of 11 with an amine or alkoxide 4, where Y=NH or O, as described in the description of Scheme 1, provides intermediate 5. Displacement of the 2-fluoro substituent of 8 with 4 provides 12. Subsequent Suzuki coupling of the aryl bromide 12 with substituted phenylboronic acid provides 5 wherein R1=Aryl.
Chloronation of the aryl sulfonic acid 7 wherein R1=OH, followed by addition of an amine or aniline provides the aryl sulfonamide intermediate 13. Displacement of the 2 fluoro substituent of 13 or 7 wherein R1=Ar, with 4 provides 5 wherein R1=sulfonamide or sulfone. 
Scheme 2b depicts Baeyer-Villiger oxidation of the intermediate 9 followed by hydrolysis provides 14. Treatment of 14 with aryl boronic acids under Evan""s conditions (see D. A. Evans et al., Tetrahedron Lett., 39, 2937-2940, 1998) provides intermediate 15. Subsequent displacement of the 2-fluoro substituent of 15 with 4 provides 5 wherein R1=aryloxy. Further protecting group and functional group manipulation of the intermediate 5 will provide the desired compounds of formula I where X is oxygen. 
Alternatively, compounds of formula I in which X is CR8R8xe2x80x2 or CO may be prepared as shown in Scheme 3. Conversion of 2 to 18 may be achieved via displacement of the 4-fluoro substituent of 2 with 16 followed by displacement of the 2-fluoro substituent of 17 with nucledphile 4. Oxidation of 18 provides 19. Deprotection and functional group manipulation of 19 provides compounds of formula I wherein X is CO. Alternatively, reductive deoxygenation of 19 affords 20. Deprotection of 20 provides intermediate 22. Alternatively, Wittig olefination of 19 provides intermediate 21. Hydrogenation, deprotection and functional group manipulation of 21 provides intermediate 22. Deprotection and functional group manipulation of 22 provides compounds of formula I where X is CR8R8xe2x80x2.
Further methods applicable to the synthesis of compounds of formula I in which X=O and R2 and R3 are independently varied as hydrogen, halogen and alkyl are described in Li et al., WO 99/00353.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substitutents. Consequently, compounds of formula I can exist in enantiomeric or diasteromeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diasteromers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods. For example, chromatographic or fractional crystallization.
A. Utilities
The compounds of the present invention are thyroid receptor ligands, and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably compounds of the present invention possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, compounds of the present invention may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene.
Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to hypothyroidism; subclinical hyperthyroidism; non-toxic goiter; atherosclerosis; thyroid hormone replacement therapy (e.g., in the elderly); malignant tumor cells containing the thyroid receptor; papillary or follicular cancer; maintenance of muscle strength and function (e.g., in the elderly); reversal or prevention of frailty or age-related functional decline (xe2x80x9cARFDxe2x80x9d) in the elderly (e.g., sarcopenia); treatment of catabolic side effects of glucocorticoids; prevention and/or treatment of reduced bone mass, density or growth (e.g., osteoporosis and osteopenia); treatment of chronic fatigue syndrome (CFS); accelerating healing of complicated fractures, e.g. distraction osteogenesis; in joint replacement; eating disorders (e.g., anorexia); treatment of obesity and growth retardation associated with obesity; treatment of depression, nervousness, irritability and stress; treatment of reduced mental energy and low selfesteem (e.g., motivation/assertiveness); improvement of cognitive function (e.g., the treatment of dementia, including Alzheimer""s disease and short term memory loss); treatment of catabolism in connection with pulmonary dysfunction and ventilator dependency; treatment of cardiac dysfunction (e.g., associated with valvular disease, myocardial infarction, cardiac hypertrophy or congestive heart failure); lowering blood pressure; protection against ventricular dysfunction or prevention of reperfusion events; treatment of hyperinsulinemia; stimulation of osteoblasts, bone remodeling and cartilage growth; regulation of food intake; treatment of insulin resistance, including NIDDM, in mammals (e.g., humans); treatment of insulin resistance in the heart; treatment of congestive heart failure; treatment of musculoskeletal impairment (e.g., in the elderly); improvement of the overall pulmonary function; skin disorders or diseases, such as glucocorticoid induced dermal atrophy, including restoration of dermal atrophy induced by topical glucocorticoids, and the prevention of dermal atrophy induced by topical glucocorticoids (such as the simultaneous treatment with topical glucocorticoid or a pharmacological product including both glucocorticoid and a compound of the invention), the restoration/prevention of dermal atrophy induced by systemic treatment with glucocdrticoids, restoration/prevention of atrophy in the respiratory system induced by local treatment with glucocorticoids, UV-induced dermal atrophy, dermal atrophy induced by aging (wrinkles, etc.), wound healing, keloids, stria, cellulite, roughened skin, actinic skin damage, lichen planus, ichtyosis, acne, psoriasis, Dernier""s disease, eczema, atopic dermatitis, chloracne, pityriasis and skin scarring.
The term treatment is also intended to include prophylactic treatment.
In addition, the conditions, diseases, and maladies collectively referenced to as xe2x80x9cSyndrome Xxe2x80x9d or Metabolic Syndrome as detailed in Johannsson J. Clin. Endocrinol. Metab., 82, 727-34 (1997), may be treated employing the compounds of the invention.
B. Combinations
The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material.
The compounds of the present invention may be employed in combination with other modulators and/or ligands of the thyroid receptor or other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents; anti-osteoporosis agents; anti-obesity agents; growth promoting agents (including growth hormone secretagogues); anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; cardiac glycosides; cholesterol/lipid lowering agents; appetite suppressants; bone resorption inhibitors; thyroid mimetics (including other thyroid receptor agonists); anabolic agents; and anti-tumor agents.
Examples of suitable anti-diabetic agents for use in combination with the compounds of the present invention include biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance(copyright)), thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, SGLT2 inhibitors, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide-1 (GLP-1), and dipeptidyl peptidase IV (DP4) inhibitors.
Examples of suitable anti-osteoporosis agents for use in combination with the compounds of the present invention include alendronate, risedronate, PTH, PTH fragment, raloxifene, calcitonin, RANK ligand antagonists, calcium sensing receptor antagonists, TRAP inhibitors, selective estrogen receptor modulators (SERM) and AP-1 inhibitors.
Examples of suitable anti-obesity agents for use in combination with the compounds of the present invention include aP2 inhibitors, PPAR gamma antagonists, PPAR delta agonists, beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merck), or CP331648 (Pfizer) or other known beta 3 agonists as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, a lipase inhibitor, such as orlistat or ATL-962 (Alizyme), a serotonin (and dopamine) reuptake inhibitor, such as sibutramine, topiramate (Johnson and Johnson) or axokine (Regeneron), other thyroid receptor beta drugs, such as a thyroid receptor ligand as disclosed in WO 97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and GB98/284425 (KaroBio), and/or an anorectic agent, such as dexamphetamine, phentermine, phenylpropanolamine or mazindol.
The compounds of the present invention may be combined with growth promoting agents, such as, but not limited to, TRH, diethylstilbesterol, theophylline, enkephalins, E series prostaglandins, compounds disclosed in U.S. Pat. No. 3,239,345, e.g., zeranol, and compounds disclosed in U.S. Pat. No. 4,036,979, e.g., sulbenox or peptides disclosed in U.S. Pat. No. 4,411,890.
The compounds of the invention may also be used in combination with growth hormone secretagogues such as GHRP-6, GHRP-1 (as described in U.S. Pat. No. 4,411,890 and publications WO 89/07110 and WO 89/07111), GHRP-2 (as described in WO 93/04081), NN703 (Novo Nordisk), LY444711 (Lilly), MK-677 (Merck), CP424391 (Pfizer) and B-HT920, or with growth hormone releasing factor and its analogs or growth hormone and its analogs or somatomedins including IGF-1 and IGF-2, or with alpha-adrenergic agonists, such as clonidine or serotinin 5-HTD agonists, such as sumatriptan, or agents which inhibit somatostatin or its release, such as physostigmine and pyridostigmine. A still further use of the disclosed compounds of the invention is in combination with parathyroid hormone, PTH(1-34) or bisphosphonates, such as MK-217 (alendronate).
A still further use of the compounds of the invention is in combination with estrogen, testosterone, a selective estrogen receptor modulator, such as tamoxifen or raloxifene, or other androgen receptor modulators, such as those disclosed in Edwards, J. P. et al., Bio. Med. Chem. Let., 9, 1003-1008 (1999) and Hamann, L. G. et al., J. Med. Chem., 42, 210-212 (1999).
A further use of the compounds of this invention is in combination with steriodal or non-steroidal progesterone receptor agonists (xe2x80x9cPRAxe2x80x9d), such as levonorgestrel, medroxyprogesterone acetate (MPA).
Examples of suitable anti-inflammatory agents for use in combination with the compounds of the present invention include prednisone, dexamethasone, Enbrel(copyright), cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors such as NSAIDs, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen(copyright), Celebrex(copyright), Vioxx(copyright)), CTLA4-Ig agonists/antagonists, CD40 ligand antagonists, IMPDH inhibitors, such as mycophenolate (CellCept(copyright)), integrin antagonists, alpha-4 beta-7 integrin antagonists, cell adhesion inhibitors, interferon gamma antagonists, ICAM-1, tumor necrosis factor (TNF) antagonists (e.g., infliximab, OR1384), prostaglandin synthesis inhibitors, budesonide, clofazimine, CNI-1493, CD4 antagonists (e.g., priliximab), p38 mitogen-activated protein kinase inhibitors, protein tyrosine kinase (PTK) inhibitors, IKK inhibitors, and therapies for the treatment of irritable bowel syndrome (e.g., Zelmac(copyright) and Maxi-K(copyright) openers such as those disclosed in U.S. Pat. No. 6,184,231 B1).
Example of suitable anti-anxiety agents for use in combination with the compounds of the present invention include diazepam, lorazepam, buspirone, oxazepam, and hydroxyzine pamoate.
Examples of suitable anti-depressants for use in combination with the compounds of the present invention include citalopram, fluoxetine, nefazodone, sertraline, and paroxetine.
For the treatment of skin disorders or diseases as described above, the compounds of the present invention may be used alone or optionally in combination with a retinoid, such as tretinoin, or a vitamin D analog.
Examples of suitable anti-hypertensive agents for use in combination with the compounds of the present invention include beta adrenergic blockers, calcium channel blockers (L-type and T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan, valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates.
Examples of suitable cardiac glycosides for use in combination with the compounds of the present invention include digitalis and ouabain.
Examples of suitable cholesterol/lipid lowering agents for use in combination with the compounds of the present invention include HMG-COA reductase inhibitors, squalene synthetase inhibitors, fibrates, bile acid sequestrants, ACAT inhibitors, MTP inhibitors, lipooxygenase inhibitors, an ileal Na+/bile acid cotransporter inhibitor, cholesterol absorption inhibitors, and cholesterol ester transfer protein inhibitors (e.g., CP-529414).
MTP inhibitors which may be employed herein in combination with one or more compounds of formula I include MTP inhibitors as disclosed in U.S. Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983 and 5,962,440 all incorporated herein by reference.
A preferred MTP inhibitor is 9-[4-[4-[[2-(2,2,2-Trifluoroethoxy)benzoyl]amino]-1-piperidinyl]butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide 
The HMG CoA reductase inhibitors which may be employed in combination with one or more compounds of formula I include mevastatin and related compounds as disclosed in U.S. Pat. No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Further HMG CoA reductase inhibitors which may be employed herein include fluvastatin, disclosed in U.S. Pat. No. 5,354,772, cerivastatin disclosed in U.S. Pat. Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Pat. Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pyrazole analogs of mevalonolactone derivatives as disclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactone derivatives, as disclosed in PCT application WO 86/03488, 6-[2-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivatives thereof, as disclosed in U.S. Pat. No. 4,647,576, Searle""s SC-45355 (a 3-substituted pentanedioic acid derivative) dichloroacetate, imidazole analogs of mevalonolactone, as disclosed in PCT application WO 86/07054, 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed in French Pat. No. 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives, as disclosed in European Patent Application No. 0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat. No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin), as disclosed in European Patent Application No.0,142,146 A2, as well as other known HMG CoA reductase inhibitors.
The squalene synthetase inhibitors which may be used in combination with the compounds of the present invention include, but are not limited to, xcex1-phosphono-sulfonates disclosed in U.S. Pat. No. 5,712,396, those disclosed by Biller et al, J. Med. Chem., 1988, Vol. 31, No. 10, pp 1869-1871, including isoprenoid (phosphinylmethyl)phosphonates, terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et al, J. Med. Chem., 1977, 20, 243-249, the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates reported by McClard, R. W. et al, J. A. C. S., 1987, 109, 5544 and cyclopropanes reported by Capson, T. L., PhD dissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table of Contents, pp 16, 17, 40-43, 48-51, as well as other squalene synthetase inhibitors as disclosed in U.S. Pat. No. 4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K., Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2, 1-40 (1996).
Bile acid sequestrants which may be used in combination with the compounds of the present invention include cholestyramine, colestipol and DEAE-Sephadex (Secholex(copyright), Policexide(copyright)), as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substituted ethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL), istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo), Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546 (disubstituted urea derivatives), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine) derivatives such as disclosed in U.S. Pat. No. 4,759,923, quaternary amine poly(diallyldimethylammonium chloride) and ionenes such as disclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterol lowering agents.
ACAT inhibitors suitable for use in combination with compounds of the invention include ACAT inhibitors as described in, Drugs of the Future 24, 9-15 (1999), (Avasimibe); xe2x80x9cThe ACAT inhibitor, Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamstersxe2x80x9d, Nicolosi et al, Atherosclerosis (Shannon, Irel). (1998), 137(1), 77-85; xe2x80x9cThe pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoproteinxe2x80x9d, Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16(1), 16-30; xe2x80x9cRP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitorxe2x80x9d, Smith, C., et al, Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; xe2x80x9cACAT inhibitors: physiologic mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animalsxe2x80x9d, Krause et al, Editor(s): Ruffolo, Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways (1995), 173-98, Publisher: CRC, Boca Raton, Fla.; xe2x80x9cACAT inhibitors: potential anti-atherosclerotic agentsxe2x80x9d, Sliskovic et al, Curr. Med. Chem. (1994), 1(3), 204-25; xe2x80x9cInhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-Nxe2x80x2-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activityxe2x80x9d, Stout et al, Chemtracts: Org. Chem. (1995), 8(6), 359-62.
Examples of suitable cholesterol absorption inhibitor for use in combination with the compounds of the invention include SCH48461 (Schering-Plough), as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
Examples of suitable ileal Na+/bile acid cotransporter inhibitors for use in combination with the compounds of the invention include compounds as disclosed in Drugs of the Future, 24, 425-430 (1999).
Examples of suitable thyroid mimetics for use in combination with the compounds of the present invention include thyrotropin, polythyroid, KB-130015, and dronedarone.
Examples of suitable anabolic agents for use in combination with the compounds of the present invention include testosterone, TRH diethylstilbesterol, estrogens, xcex2-agonists, theophylline, anabolic steroids, dehydroepiandrosterone, enkephalins, E-series prostagladins, retinoic acid and compounds as disclosed in U.S. Pat. No. 3,239,345, e.g., Zeranol(copyright); U.S. Pat. No. 4,036,979, e.g., Sulbenox(copyright) or peptides as disclosed in U.S. Pat. No. 4,411,890.
The aforementioned patents and patent applications are incorporated herein by reference.
The above other therapeutic agents, when employed in combination with the compounds of the present invention, may be used, for example, in those amounts indicated in the Physicians"" Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
Where the compounds of the invention are utilized in combination with one or more other therapeutic agent(s), either concurrently or sequentially, the following combination ratios and dosage ranges are preferred:
When combined with a hypolypidemic agent, an antidepressant, a bone resorption inhibitor and/or an appetite suppressant, the compounds of formula I may be employed in a weight ratio to the additional agent within the range from about 500:1 to about 0.005:1, preferably from about 300:1 to about 0.01:1.
Where the antidiabetic agent is a biguanide, the compounds of formula I may be employed in a weight ratio to biguanide within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 2:1.
The compounds of formula I may be employed in a weight ratio to a glucosidase inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 50:1.
The compounds of formula I may be employed in a weight ratio to a sulfonylurea in the range from about 0.01:1 to about 100:1, preferably from about 0.2:1 to about 10:1.
The compounds of formula I may be employed in a weight ratio to a thiazolidinedione in an amount within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
The thiazolidinedione may be employed in amounts within the range from about 0.01 to about 2000 mg/day, which may optionally be administered in single or divided doses of one to four times per day.
Further, where the sulfonylurea and thiazolidinedione are to be administered orally in an amount of less than about 150 mg, these additional agents may be incorporated into a combined single tablet with a therapeutically effective amount of the compounds of formula I.
Metformin, or salt thereof, may be employed with the compounds of formula I in amounts within the range from about 500 to about 2000 mg per day, which may be administered in single or divided doses one to four times daily.
The compounds of formula I may be employed in a weight ratio to a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-alpha/gamma dual agonist, an SGLT2 inhibitor and/or an aP2 inhibitor within the range from about 0.01:1 to about 100:1, preferably from about 0.5:1 to about 5:1.
An MTP inhibitor may be administered orally with the compounds of formula I in an amount within the range of from about 0.01 mg/kg to about 100 mg/kg and preferably from about 0.1 mg/kg to about 75 mg/kg, one to four times daily.
A preferred oral dosage form, such as tablets or capsules, may contain the MTP inhibitor in an amount of from about 1 to about 500 mg, preferably from about 2 to about 400 mg, and more preferably from about 5 to about 250 mg; administered on a regimen of one to four times daily.
For parenteral administration, the MTP inhibitor may be employed in an amount within the range of from about 0.005 mg/kg to about 10 mg/kg and preferably from about 0.005 mg/kg to about 8 mg/kg, administered on a regimen of one to four times daily.
A HMG CoA reductase inhibitor may be administered orally with the compounds of formula I within the range of from about 1 to 2000 mg, and preferably from about 4 to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain the HMG CoA reductase inhibitor in an amount from about 0.1 to about 100 mg, preferably from about 5 to about 80 mg, and more preferably from about 10 to about 40 mg.
A squalene synthetase inhibitor may be administered with the compounds of formula I within the range of from about 10 mg to about 2000 mg and preferably from about 25 mg to about 200 mg.
A preferred oral dosage form, such as tablets or capsules, will contain the squalene synthetase inhibitor in an amount of from about 10 to about 500 mg, preferably from about 25 to about 200 mg.
The compounds of formula I of the invention can be administered orally or parenterally, such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, in an effective amount within the dosage range of abut 0.01 xcexcg/kg to about 1000 xcexcg/kg, preferably about 0.1 xcexcg/kg to 100 xcexcg/kg, more preferably about 0.2 xcexcg/kg to about 50 xcexcg/kg (or form about 0.5 to 2500 mg, preferably from about 1 to 2000 mg) in a regimen of single, two or four divided daily doses.
The compounds of the formula I can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; bucally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally.
Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula I can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer""s solution, an isotonic sodium chloride solution, or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
It will be understood that the specific dose level and frequency of dosage for any particular subject can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.